The skin at times is afflicted with a variety of inflammatory and non-inflammatory disorders. One such disorder is acne, a common disease characterized by various types of lesions. The areas affected typically are areas of the skin where sebaceous glands are largest, most numerous, and most active. The lesions associated with acne are usually categorized as either non-inflammatory or inflammatory. Non-inflammatory lesions include comedones. Comedones appear in two forms, open and closed. Comedones are thought to arise from abnormal follicular differentiation. Instead of undergoing shedding and discharge through the follicular orifice, abnormal desquamated cells (keratinocytes) become unusually cohesive, forming a microcomedone or a microscopic hyperkeratotic plug in the follicular canal. The progression of these microcomedones leads to visible comedones.
For closed comedones, the first sign of inflammation appears along the follicular wall, which then ruptures. Once rupture occurs, the contents of the comedone are extruded into the dermis and cause an increased inflammatory response. Depending on the depth in the dermis and the degree of inflammation, the inflammatory lesion will appear as a pustule, papule, nodule, or cyst. Papules are inflamed, red, tender bumps with no head that range from 2 to 5 mm in diameter. Pustules are papules that are superficial and contain grossly purulent material, that is they have a head with a white or yellow center. Nodules are large, hard bumps 5 mm or more in diameter present under or within the surface of the skin, which can be painful and can last for many months. Cysts are similar to nodules but are pus-filled.
For the purposes of this specification, and unless specified, the term “acne” includes all known types of acne. Types of acne include, for example, acne vulgaris, cystic acne, bromide acne, chlorine acne, comedonal acne, acne conglobata, acne cosmetica, acne estivalis, acne fulminans, halogen acne, iodide acne, acne keloidalis, acne mechanica, nodular acne, non-inflammatory acne, acne papulosa, pomade acne, premenstral acne, acne pustulosa, acne varioliformis, acne venenata, propionic acne, acne excoriee, gram negative acne, steroid acne, inflammatory acne, and nodulocystic acne.
In its mildest form, acne is a more or less superficial disorder characterized by slight, spotty skin irritations involving comedones. In such cases, ordinary skin hygiene, which may include the use of topical keratolytics, typically proves to be a satisfactory treatment. In the more inflammatory types of acne, however, papules; pustules; nodules and cysts; and in extreme cases, canalizing, inflamed and infected sacs, appear. Without effective treatment, these lesions may become extensive and leave permanent, disfiguring scars.
The etiology of acne is multi-factorial. The disease is thought to originate primarily due to increased production of sebum, hypercomification of the infundibulum of pilosebaceous glands, proliferation of microbial flora especially Propionibacterium acnes, and subsequent inflammation. P. acnes organisms primarily colonize the sebaceous follicles found in the skin, and thus are in a location that is physically sequestered from the skin tissue. Current theories on the pathophysiology of acne hold that the inflammation of acne is due, in part, to an immune reaction to the bacterium or to extracellular products produced in response to the presence of the bacterium, rather than being due to presence of the bacterium itself. Therefore, treatments that are aimed solely at reduction in numbers of P. acnes organisms are generally not very effective in long-term treatment of acne. The normal process of epidermal maturation, called keratinization, involves the growing and shedding of cells that line the pores and glands of the skin. In acne, this process is disrupted, causing an overproduction of epithelial cells (hyperkeratosis) in the follicular infundibulum, forming a blockage of the pore.
Mild acne is typically treated with topical cleansers and benzoyl peroxide. Moderate inflammatory acne is often treated with cleansers and keratolytic or comedolytic agents such as retinoids (tretinoin, adapalene or tazarotene), salicylic acid or alpha-hydroxy acids, often in combination with topical or systemic antibiotics. Systemically administered antibiotics, including tetracycline, minocycline, doxycycline, erythromycin, and azithromycin, have been used successfully to treat pustular or papular acne.
Another important skin disorder is rosacea. Rosacea is distinct from acne, although it is sometimes referred to as acne rosacea. Rosacea most commonly affects the skin of the nose and central facial area, and in severe cases involves an extensive area of the face. Forms of acne rosacea include erythematotelangiectatic rosacea, steroid-induced rosacea, papular rosacea, pustular rosacea, ocular rosacea, rhinophymatous rosacea, edematous rosacea, perioral dermatitis, and granulomatous rosacea. Examples of other skin conditions include psoriasis, atopic dermatitis, eczema, irritant contact dermatitis, allergic contact dermatitis, and precancerous skin conditions such as actinic keratosis.
Azithromycin is the generic name for 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, a broad spectrum antibiotic derived from erythromycin A. It was independently discovered by Bright, U.S. Pat. No. 4,474,768 and Kobrehel, U.S. Pat. No. 4,517,359, where it was referred to by the name of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A. Bright and Kobrehel disclosed azithromycin as a hygroscopic form. Allen, U.S. Pat. No. 6,268,489, discloses a non-hygroscopic dihydrate form of azithromycin. Both the monohydrate form and the dihydrate form are effective in treating bacterial infections when administered systemically in a short course of therapy involving, typically, one to five oral doses.
Several scientific articles have published studies establishing the efficacy of azithromycin in treating inflammatory lesions (papules and pustules) of acne. Femandez-Obregon, International Journal of Dermatology, 39:45-50 (2000), discloses that azithromycin administered in a pulse-dose regimen of 250 mg three times per week is as effective as other antibiotics tested in treating lesions of inflammatory acne. Fernandez-Obregon reported that 19% of the 21 subjects in the study experienced side effects, including 3 cases of gastrointestinal discomfort and one case of vaginitis. Kus et al, Clinical and Experimental Dermatology, 30:215-220 (2005), disclosed that azithromycin dosed at 500 mg for 3 consecutive days per week for 4 weeks, then 2 consecutive days per week for 4 weeks, and then once weekly for 4 weeks was as effective as doxycycline in the treatment of acne. Kus reported that 25 subjects were administered azithromycin in this study. Of these 25, two left the study due to non-compliance and two others left the study due to gastrointestinal side effects.
Similar results have been obtained in other studies of pulse-dosing of azithromycin for the treatment of acne. In Gruber, et al, Journal of Chemotherapy, 10(6):469-473 (1998), azithromycin was pulse-dosed at 500 mg/day for 4 days in four cycles every 10 days. This regimen proved to be efficacious in the treatment of acne and was associated with a gastrointestinal side effect rate of about 10%. Kapadia, International Journal of Dermatology, 43:766-767 (2004), reported successful treatment of acne with 500 mg azithromycin administered three times per week. Adverse events were reported in 11% of subjects. Elewski, European Academy of Dermatology and Venereology, 14:422-430, administered azithromycin at 500 mg on day 1, followed by 250 mg/day for 4 consecutive days beginning on the 1st and 15th day of each month for 3 months. Elewski reported that all patients treated with this azithromycin regimen showed improvement in their acne and only one of twenty subjects experienced gastrointestinal side effects. Elewski further disclosed that intermittent azithromycin offers an effective and rational alternative to systemic antibiotics traditionally used for the management of patients with acne vulgaris or rosacea and could result in a positive impact on patients's quality of life compared with continuous, daily treatment regimens. As stated by Elewski, the pulse dosing regimen for administering azithromycin has been utilized because the long half-life of azithromycin permits the medication to remain in intracellular compartments for prolonged periods at levels higher than the minimum inhibitory concentration for many pathogens.
Recent trends in dosage administration of azithromycin for treatment of skin diseases have been towards higher doses provided in a pulse regimen. Pfizer's Clinical Trial No. NCT00392223 begun in December 2006 and ongoing at the present time tests the efficacy in treating acne with azithromycin in a pulse dosage regimen of 2 grams of azithromycin administered once weekly for 8 weeks.
Tetracyclines are broad spectrum antibiotics that provide their antimicrobial effect by inhibiting protein synthesis by binding to the 30S ribosomal unit. Ashley, U.S. Pat. No. 7,211,267, discloses methods of treating acne by administering a tetracycline compound, such as tetracycline, minocycline, oxytetracycline, and doxycycline. Ashley discloses that tetracycline compounds, which are well known antibiotics, are effective in the treatment of acne even when administered in amounts below that at which the compounds are effective against bacteria. Ashley suggests that treatment with low levels of tetracyclines may cause fewer undesirable side effects than occur with conventional dosages of tetracyclines.
Azithromycin is a member of the macrolide family of antibiotics. In contrast to the tetracyclines, azithromycin and other macrolides such as erythromycin exert their effect by inhibiting RNA-dependent protein synthesis by reversibly binding to the 50S ribosomal unit. Azithromycin has not been shown to be effective in the treatment of acne or other skin disorders at dosages below that which provide the minimum inhibitory concentration in plasma for bacteria associated with acne, such as P. acnes. 